Magnetic resonance imaging (MRI) is a rapidly developing diagnostic imaging modality, which detects magnetic resonance signals emitted from water molecules after irradiation of low electromagnetic energy into a sample. Magnetic resonance imaging allows repeatable acquisitions of non-invasive magnetic resonance images to study tissue anatomy with high resolution for a short time, and therefore, it is known as the most suitable method for diagnosing a patient's disease and monitoring drug treatment. Signal intensity of magnetic resonance imaging is determined by two time parameters, which are T1 and T2 relaxation time and by proton density of water molecule from spin density. With regard to the contrast of magnetic resonance imaging, magnetic resonance images of a sample are controlled by a contrast agent.
Gadolinium (Gd) agents are representative of the paramagnetic T1 contrast agent. However, the gadolinium (Gd) agent itself is highly toxic, and therefore, its safety must be improved it the form of chelates. For instance, a MRI contrast agent (Gd-DTAP) prepared by chelating Gd with diethylenetriamine pentaacetic acid (DTAP) is frequently used.
However, most T1 contrast agents including Gd-DTPA are not specific to organs, tissues, or particular cells, but most of them are contrast agents for imaging blood vessels of the tissues. Further, the conventional contrast agents nave a short retention time in vivo, and therefore, efforts to improve the retention time have been made.
Meanwhile, melanins are biopolymers that are widely distributed in many parts of living organisms such as plants, animals, and protista, and are usually categorized into black-brown eumelanins and yellow-reddish pheomelanins. Eumelanins are derived from 3,4-dihydrozy-L-phenyl alanine (L-DOPA) or 2-(3,4-dihydroxyphenyl)ethylamine (dopamine), and pheomelanins are derived from L-DOPA or dopamine in the presence of mercapto group (—SH)-containing compounds such as cysteine, glutathione, etc. Eumelanins are predominantly found in mammals, and are known to be biopolymers having irregular polymeric structures, including the indole units which are formed from catecholamines by intramolecular addition of the amino groups to the oxidatively generated o-quinones.
Melanoma in the body is Known to show strong T1-MRI signals through, a coordinate bond with paramagnetic metal ions in the body, suggesting detection of melanoma in the body by MRI and possibility of MRI probes by using melanin.
However, it is difficult to obtain pure melanins, because many biological materials such as proteins other than melanins are also obtained when obtained from natural sources. In addition, even though the biological materials are removed by purification, melanin particles themselves are damaged to reduce their contrasting effect. Meanwhile, melanins which are obtained by the conventional synthetic method are not dispersed in water, and thus there was a limitation in their use as a biological contrast agent. In particular, it is difficult to use the melanins in vivo because of the low dispersibility in water. In addition, although it injected into the body, they are precipitated/aggregated, or rapidly excreted from the body. Thus, there is a disadvantage that a desired contrasting effect cannot be obtained.
Accordingly, the present inventors prepared melanin nanoparticles having a predetermined size and shape, and formed coordinate bonds between the melanin nanoparticles and paramagnetic ions, and modified the surface of the melanin nanoparticles with PEGs. They found that these melanin nanoparticles have good dispersibility in water, no cytotoxicity, and a long retention time in vivo, so as to be usefully applied as an MRI contrast agent, thereby completing the present invention.